Quinolinones as prostaglandin receptor ligands

ABSTRACT

This invention encompasses a method for treating a prostaglandin E mediated disease or condition comprising administering to a mammalian patient in need of such treatment a compound of Formula (A) in an amount that is effective to treat the prostaglandin E mediated disease or condition

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application No. PCT/CA02/01914, filed Dec. 11, 2002, whichclaims priority under 35 U.S.C. 119 to 60/340,439, filed Dec. 14, 2001.

BACKGROUND OF THE INVENTION

This invention relates to compounds and methods for treatingprostaglandin E mediated diseases, and certain pharmaceuticalcompositions thereof. More particularly, the compounds of the inventionare structurally different from NSAIDs and opiates, and are antagonistsof the pain and inflammatory effects of E-type prostaglandins.

Two review articles describe the characterization and therapeuticrelevance of the prostanoid receptors as well as the most commonly usedselective agonists and antagonists: Eicosanoids From Biotecnology toTherapeutic Applications, Folco, Samuelsson, Maclouf, and Velo eds,Plenum Press, New York, 1996, chap. 14, 137-154 and Journal of LipidMediators and Cell Signalling, 1996, 14, 83-87. An article from TheBritish Journal of Pharmacology (1994, 112, 735-740) suggests thatProstaglandin E₂ (PGE₂) exerts allodynia through the EP₁ receptorsubtype and hyperalgesia through EP₂ and EP₃ receptors in the mousespinal cord.

Thus, selective prostaglandin ligands, agonists or antagonists,depending on which prostaglandin E receptor subtype is being considered,have anti-inflammatory, antipyretic and analgesic properties similar toa conventional non-steroidal anti-inflammatory drug, and in addition,inhibit hormone-induced uterine contractions and have anti-cancereffects. These compounds have a diminished ability to induce some of themechanism-based side effects of NSAIDs which are indiscriminatecyclooxygenase inhibitors. In particular, the compounds have a reducedpotential for gastrointestinal toxicity, a reduced potential for renalside effects, a reduced effect on bleeding times and a lessened abilityto induce asthma attacks in aspirin-sensitive asthmatic subjects.

In The American Physiological Society (1994, 267, R289-R-294), studiessuggest that PGE2-induced hyperthermia in the rat is mediatedpredominantly through the EP1 receptor. World patent applications WO96/06822 (Mar. 7, 1996), WO 96/11902 (Apr. 25, 1996) and EP 752421-A1(Jan. 08, 1997) disclose compounds as being useful in the treatment ofprostaglandin mediated diseases.

SUMMARY OF THE INVENTION

This invention encompasses a method for treating a prostaglandin Emediated disease or condition comprising administering to a mammalianpatient in need of such treatment a compound of Formula A:

in an amount that is effective to treat the prostaglandin E mediateddisease or condition.

DETAILED DESCRIPTION OF THE INVENTION

This invention encompasses a method for treating a prostaglandin Emediated disease or condition comprising administering to a mammalianpatient in need of such treatment a compound of Formula A:

or a pharmaceutically acceptable salt, hydrate, ester or tautomerthereof, wherein:

-   R¹ is selected from the group consisting of:

(1) hydrogen,

(2) halo,

(3) hydroxy,

(4) C₁₋₆alkyl,

(5) C₁₋₆alkenyl,

(6) C₁₋₆alkoxy,

(7) C₁₋₆alkyl-S(O)_(m)—, wherein m is 0, 1, 2 or 3

(8) C₁₋₆alkyl-C(O)—

(7) C₁₋₆alkoxy-C(O)—

(9) C₁₋₆alkyl-C(O)—O—

(10) aryl,

(11) aralkyl,

(12) aryloxy,

(13) aralkoxy,

(14) arylthio,

(15) aroyl,

(16) aroyloxy, and

(17) N(R⁸)2,

-   wherein the alkyl , alkenyl and aryl portions of items (4)-(16)    above are optionally substituted from one up to the maximum number    of substituable positions with a member independently selected from    the group consisting of: halo, heterocycle, C₁₋₆alkoxy,    C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2C₁₋₆alkyl-C(O)—,    C₁₋₆alkoxy-C(O), C₁₋₆alkyl-C(O)—O, carboxy, hydroxy and aralkoxy,    the alkyl portions of said C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(k)—,    C₁₋₆alkyl-C(O)—, C₁₋₆alkoxy-C(O) and C₁₋₆alkyl-C(O)—O groups    optionally substituted with 1-3 substituents independently selected    from: halo and hydroxy,-   said aryl portions of items (10)-(16) above further optionally    substituted from one up to the maximum number of substituable    positions with C₁₋₆alkyl, optionally substituted with 1-3    substituents independently selected from the group consisting of:    halo and hydroxy;-   R² is selected from the group consisting of:

(1) benzyl, optionally substituted with 1-3 substituents independentlyselected from the group consisting of:

-   -   (a) halo,    -   (b) aryl,    -   (c) aryloxy,    -   (d) aryl-S(O)_(k)—, wherein k is 0, 1 or 2,    -   (e) heterocycle,    -   (f) aralkyl,    -   (g) aroyl,    -   (h) aroyloxy,    -   (i) C₁₋₆alkyl,    -   (j) C₁₋₆alkenyl,    -   (k) C₁₋₆alkoxy,    -   (l) C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2,    -   (m) C₁₋₆alkyl-C(O)—,    -   (n) C₁₋₆alkoxy-C(O),    -   (o) C₁₋₆alkyl-C(O)—O—,    -   (p) carboxy,    -   (q) hydroxy,    -   (r) N(R8)₂,    -   (s) SO₂R⁸, and    -   (t) SO₂N(R⁸)₂

-   wherein the alkyl , alkenyl, aryl and heterocycle portions of items    (b)-(o) above are optionally substituted from one up to the maximum    number of substituable positions with a member independently    selected from the group consisting of: halo, heterocycle,    C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or    2C₁₋₆alkyl-C(O)—, C₁₋₆alkoxy-C(O)—, C₁₋₆alkyl-C(O)—O—, aralkoxy,    carboxy and hydroxy, the alkyl portions of said C₁₋₆alkoxy,    C₁₋₆alkyl-S(O)_(k)—, C₁₋₆alkyl-C(O)—, C₁₋₆alkoxy-C(O) and    C₁₋₆alkyl-C(O)—O groups optionally substituted with 1-3 substituents    independently selected from halo and hydroxy;

-   said aryl and heterocycle portions of items (b)-(h) above further    optionally substituted from one up to the maximum number of    substituable positions with C₁₋₆alkyl optionally substituted with    1-3 substituents independently selected from the group consisting    of: halo and hydroxy;

(2) C₁₋₇alkyl or C₁₋₆alkenyl, each optionally substituted with 1-3groups independently selected from the group consisting of: halo,hydroxy, C₃₋₆cycloalkyl, aryl and heterocycle, said aryl and heterocycleoptionally substituted with 1-3 substituents independently selectedfrom:

-   -   (a) halo,    -   (b) hydroxy,    -   (c) aryl, optionally substituted with 1-3 halo groups, and    -   (d) C₁₋₆alkyl, optionally substituted independently with 1-3        halo or hydroxy groups,

-   except that when R² is methyl monosubstituted with aryl as phenyl    then R² is defined as in (1) above, and

(3) aroyl, optionally substituted with aryloxy or arylthio, said aryloxyor arylthio optionally substituted with 1-3 halo groups;

-   R³ is selected from the group consisting of:

(1) C₁₋₆alkyl, C₂₋₆alkenyl or C₃₋₆alkynyl, each optionally substitutedwith 1-3 halo groups,

(2) aryl, optionally substituted with 1-3 halo groups, and

(3) aralkyl, optionally substituted with a substituent independentlyselected from the group consisting of: C₁₋₆alkylsulfonyl and halo,

-   R⁴, R⁵, R⁶ and R⁷ are each independently selected from the group    consisting of:

(1) hydrogen,

(2) halo, and

(3) C₁₋₆alkyl, optionally substituted with 1-3halo groups,

-   or R3 and R4 may be joined together with the atoms to which they are    attached to form a monocyclic ring as shown in Formula A′:

-   wherein R¹⁴ is selected from the groups consisting of: halo,    C₁₋₆alkyl or aryl, wherein C₁₋₆alkyl and aryl are optionally    substituted with 1-3 halo groups; and-   R⁸ is selected from the group consisting of H, C₁₋₆alkyl,    C₁₋₆alkenyl and C₁₋₆alkyl-C(O)—, the alkyl and alkenyl portions of    which are optionally substituted with 1-3 halo groups,-   in an amount which is effective for treating the prostaglandin E    mediated disease.

For purposes of this Specification, “pharmaceutically acceptablehydrate” means the compounds of the instant invention crystallized withone or more molecules of water to form a hydrated form.

For purposes of this Specification, the term “pharmaceuticallyacceptable ester” means ester derivative formed at any carboxylic acidof the compounds of the present invention, such as Example 55that mayact as a prodrug which, when absorbed into the bloodstream of awarm-blooded animal, may cleave in such a manner as to release the drugform and permit the drug to afford improved therapeutic efficacy.

For purposes of this Specification, “pharmaceutically acceptabletautomer” means any tautomeric form of any compound of the presentinvention. For example, the compounds of the present invention wouldinclude the tautomeric forms shown below:

For purposes of this Specification, “treating” a prostaglandin Emediated disease or condition encompasses not only treating a patientwith symptoms of the disease or condition but also “prophylacticallytreating” a patient prior to that patient manifesting symptoms of thedisease or condition to prevent said disease or condition. The term“treating” a prostaglandin disease or condition also encompassespreventing the onset or progression of a prostaglandin E mediateddisease or condition.

An embodiment of the invention encompasses the above method wherein theprostaglandin E mediated disease or condition is selected from the groupconsisting of:

(1) pain, fever or inflammation associated with rheumatic fever,influenza or other viral infections, common cold, low back and neckpain, skeletal pain, postpartum pain, dysmenorrhea, headache, migraine,toothache, sprains and strains, myositis, neuralgia, synovitis,arthritis, including rheumatoid arthritis, degenerative joint diseases(osteoarthritis), gout and ankylosing spondylitis, bursitis, bumsincluding radiation and corrosive chemical injuries, sunburns, painfollowing surgical and dental procedures as well as immune andautoimmune diseases;

(2) cellular neoplastic transformations or metastic tumor growth;

(3) diabetic retinopathy and tumor angiogenesis;

(4) prostanoid-induced smooth muscle contraction associated withdysmenorrhea, premature labor, asthma or eosinophil related disorders;

(5) Alzheimer's disease;

(6) glaucoma;

(7) bone loss;

(8) osteoporosis;

(9) promotion of bone formation;

(10) Paget's disease;

(11) cytoprotection in peptic ulcers, gastritis, regional enteritis,ulcerative colitis, diverticulitis or other gastrointestinal lesions;

(12) GI bleeding and patients undergoing chemotherapy;

(13) coagulation disorders selected from hypoprothrombinemia,haemophilia and other bleeding problems;

(14) kidney disease;

(15) thrombosis;

(16) occlusive vascular disease;

(17) presurgery;

(18) anti-coagulation;

(19) neuropathic pain; and

(20) urinary incontinence.

Another embodiment of the invention encompasses the above method whereinthe prostaglandin E mediated disease is selected from the groupconsisting of: pain, fever or inflammation associated with rheumaticfever, influenza or other viral infections, common cold, low back andneck pain, skeletal pain, post-partum pain, dysmenorrhea, headache,migraine, toothache, sprains and strains, myositis, neuralgia,synovitis, arthritis, including rheumatoid arthritis, degenerative jointdiseases (osteoarthritis), gout and ankylosing spondylitis, bursitis,burns including radiation and corrosive chemical injuries, sunburns,pain following surgical and dental procedures as well as immune andautoimmune diseases.

Another embodiment of the invention encompasses the above method whereinthe prostaglandin E mediated disease or condition is pain, fever orinflammation associated with dysmenorrhea.

Another embodiment of the invention encompasses the above method fortreating a prostaglandin E mediated disease or condition comprisingadministering to a mammalian patient in need of such treatment acompound of Formula A:

or a pharmaceutically acceptable salt thereof, said variables as definedabove, wherein the compound of Formula A is co-administered with otheragents or ingredients.

Within this embodiment is encompassed the method wherein the compound ofFormula A is co-administered with another agent or ingredient selectedfrom the group consisting of:

(1) an analgesic selected from acetaminophen, phenacetin, aspirin, anarcotic;

(2) a cyclooxygenase-2 selective nonsteroidal anti-inflammatory drug ora conventional nonsteroidal anti-inflammatory drug;

(3) caffeine;

(4) an H₂-antagonist;

(5) aluminum or magnesium hydroxide;

(6) simethicone;

(7) a decongestant selected from phenylephrine, phenylpropanolamine,pseudophedrine, oxymetazoline, ephinephrine, naphazoline,xylometazoline, propylhexedrine, or levo-desoxyephedrine;

(8) an antiitussive selected from codeine, hydrocodone, caramiphen,carbetapentane and dextramethorphan;

(9) another prostaglandin ligand selected from misoprostol, enprostil,rioprostil, ornoprostol and rosaprostol; a diuretic; and

(10) a sedating or non-sedating antihistamine. Examples of COX-2inhibitors are disclosed in U.S. Pat. Nos. 5,474,995; 5,633,272; and5,466,823; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691,and WO 95/0051.

Also, within this embodiment is encompassed the method wherein thecompound of Formula A is co-administered with a cyclooxygenase-2selective nonsteroidal anti-inflammatory drug or a conventionalnonsteroidal anti-inflammatory drug.

Also within this embodiment is encompassed the method wherein thecompound of Formula A is co-administered with a conventionalnonsteroidal anti-inflammatory drug selected from the group consistingof: aspirin, ibuprofen, naproxen, and ketoprofen.

Also within this embodiment is encompassed the method wherein thecompound is co-administered with a cyclooxygenase-2 selectivenonsteroidal anti-inflammatory drug selected from rofecoxib, etoricoxib,valdecoxib, parecoxib and celecoxib.

Another embodiment of the invention encompasses the method for treatinga prostaglandin E mediated disease or condition comprising administeringto a mammalian patient in need of such treatment a compound of Formula Aor a pharmaceutically acceptable salt thereof, wherein R² is benzyl,optionally substituted with 1-3 substituents independently selected fromthe group consisting of:

-   -   (a) halo,    -   (b) aryl,    -   (c) aryloxy,    -   (d) aryl-S(O)k, wherein k is 0, 1 or 2,    -   (e) heterocycle,    -   (f) aralkyl,    -   (g) aroyl,    -   (h) aroyloxy,    -   (i) C₁₋₆alkyl,    -   (j) C₁₋₆alkenyl,    -   (k) C₁₋₆alkoxy,    -   (l) C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2,    -   (m) C₁₋₆alkyl-C(O)—,    -   (n) C₁₋₆alkoxy-C(O),    -   (o) C₁₋₆alkyl-C(O)—O—,    -   (p) carboxy,    -   (q) hydroxy, and    -   (r) N(R8)2,        wherein the alkyl , alkenyl, aryl and heterocycle portions of        items (b)-(o) above are optionally substituted from one up to        the maximum number of substituable positions with a member        independently selected from the group consisting of: halo,        heterocycle, C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(k)—, C₁₋₆alkyl-C(O)—,        C₁₋₆alkoxy-C(O)—, C₁₋₆alkyl-C(O)—O—, aralkoxy, carboxy and        hydroxy, the alkyl portions of said C₁₋₆alkoxy,        C₁₋₆alkyl-S(O)_(k)—, C₁₋₆alkyl-C(O)—, C₁₋₆alkoxy-C(O) and        C₁₋₆alkyl-C(O)—O groups optionally substituted with 1-3        substituents independently selected from halo and hydroxy;        said aryl and heterocycle portions of items (b)-(h) above        further optionally substituted from one up to the maximum number        of substituable positions with C₁₋₆alkyl optionally substituted        with 1-3 substituents independently selected from the group        consisting of: halo and hydroxy.

Another embodiment of the invention encompasses the method for treatinga prostaglandin E mediated disease or condition comprising administeringto a mammalian patient in need of such treatment a compound of Formula Aor a pharmaceutically acceptable salt thereof, wherein R² is mono-, dior tri substituted benzyl, wherein the substituents are independentlyselected from the group consisting of:

-   -   (a) aryl,    -   (b) aryloxy,    -   (c) aryl-S(O)_(k)—, wherein k is 0, 1 or 2,    -   (d) heterocycle,    -   (e) aralkyl,    -   (f) aroyl, and    -   (g) aroyloxy,        the aryl and heterocycle portions of items (a)-(g) above are        optionally substituted from one up to the maximum number of        substituable positions with a member independently selected from        the group consisting of: halo, C₁₋₆alkyl, C₁₋₆alkoxy,        C₁₋₆alkyl-S(O)_(k)—, C₁₋₆alkyl-C(O)—, C₁₋₆alkoxy-C(O)—,        C₁₋₆alkyl-C(O)—O—, aralkoxy, carboxy and hydroxy, the alkyl        portions of said C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(k)—,        C₁₋₆alkyl-C(O)—, C₁₋₆alkoxy-C(O) and C₁₋₆alkyl-C(O)—O groups        optionally substituted with 1-3 substituents independently        selected from halo and hydroxy.

Another embodiment of the invention encompasses the method for treatinga prostaglandin E mediated disease or condition comprising administeringto a mammalian patient in need of such treatment a compound of Formula Aor a pharmaceutically acceptable salt thereof, wherein R² is mono-, di-or tri-substituted benzyl, with the proviso that at least one of thesubstituents is attached to the benzyl group at the 4-position.

Another embodiment of the invention encompasses the method for treatinga prostaglandin E mediated disease or condition comprising administeringto a mammalian patient in need of such treatment a compound of Formula Aor a pharmaceutically acceptable salt thereof, wherein R¹ is methoxy,difluoromethoxy, hydroxy or amino.

Another embodiment of the invention encompasses the method for treatinga prostaglandin E mediated disease or condition comprising administeringto a mammalian patient in need of such treatment a compound of Formula Aor a pharmaceutically acceptable salt thereof, wherein R3 is benzyl,phenyl, ethyl, propyl, methyl or allyl.

The present invention also encompasses the method for treating aprostaglandin E mediated disease or condition comprising administeringto a mammalian patient in need of such treatment a compound from thefollowing tables:

R¹ R³ R⁴ R⁵ R⁶ R⁷ R¹¹ R¹² R¹³ OMe benzyl H H H H H H H OH 4-MeSO2benzylH H H H H H H OH benzyl H H H H H H 4-MeSO2 OH n-butyl H H H H H H H Mebenzyl H H H H H H H OH iso-propyl H H H H H H H OH Me H H H H H H H OHphenyl H H H H H H H OH Me H H H H H H Me OH benzyl Me H H H H H H OHethyl Me H H H H H H OH Me H Cl H H H H phenyl OH Me H H Cl H H H3-Cl-4-F-phenyl NH2 Me H H H H F H 3-Cl-4-F-phenyl OH Me H H H H H H OMeOH Me H H H H H H CO2Me OH Me H H H H H CO2H H OH Me H H H H H H CO2H OHMe H H H H H H SMe OH Me H H H H Me H H OH Me H H H H H Me H OH Me H H HH H H OPh OH Me H H H H H H Ph OH Me H H H H H H CF3 OH Me H H H H H H FOH Me H H H H H H NMe2 OH Me H H H H H H isopropyl OH ethyl H H H H H HMe OH Me H H H H H H 3,4-(OCF2H) OH Me H H H H H H phenylsulfonyl OH MeH H H H H H 4-Cl-thiophenoxy OH Me H H H H H H benzoyl OH Me H H H H H Hbromo OH Me H H H H H H 3-Cl-4-F-phenyl OCF2H Me H H H H H H phenyl OHMe H H H H H H 5-(2-Et-pyridinyl) OH Me H H H H H 5-(2-Et-pyridinyl) HOH Me H H H H H 4-CF3-phenyl H OH Me H H H H H H 4-CF3-phenyl OH Me H HH H H H 4-tert-butylphenyl OH Me H H H H H H 4-acetylphenyl OH Me H H HH H 4-acetylphenyl H OH Me H H H H H H 4-carboxyphenyl OH Me H H H H H H4-Et-phenyl OH Me H H H H H bromo H OMs Me H H H H H H phenyl OH Me H HH H H phenyl H OH Me H H H H H 4-carboxyphenyl H OH Me H H H H H4-Cl-phenyl H OH Me H H H H H 3-thienyl H OH Me H H H H H 4-OCF3-phenylH OH Me H H H H H H 3-thienyl OH Me H H H H H H 2-thienyl OH Me H H H HH H 2-naphthyl OH Me H H H H H H 4-Cl-phenyl OH Me H H H H H H4-OCF3-phenyl OH Me H H H H H H 2-benzothiophene OH Me H H H H H H4-F-phenyl OH Me H H H H H 2-F-phenyl H OH Me H H H H H H 4-Me-phenyl OHMe H H H H H H 4-benzyloxyphenyl OH Me H H H H H H α-OH-a-Me-benzyl OHMe H H H H H H 1-naphthyl OH Me H H H H H H 2-F-phenyl OH Me H H H H H H3-F-phenyl OH Me H H H H H H 3-Cl-phenyl OH Me H H H H H 3-Cl-phenyl HOH Me H H H H H 3-F-phenyl H OH Me H H H H H H 4-Cl-phenylsulfonyl OH MeH H H H H H α-OH-a-Me-4-Cl-benzyl OH Me H H H H H H 3-Cl-4-F-phenyl OHethyl H H H H H H 3-Cl-4-F-phenyl OH allyl H H H H H H 3-Cl-4-F-phenylOH n-propyl H H H H H H 3-Cl-4-F-phenyl OH Me H H H H H H 4-MeSO2 OH MeH H H H H 2-benzothiophene H OH 4-Cl-benzyl H H H H H H 3-Cl-4-F-phenylNH2 Me H H H H H H 3-Cl-4-F-phenyl 2-(2-pyridinyl)ethoxy Me H H H H H H3-Cl-4-F-phenyl carbethoxymethoxy Me H H H H H H 3-Cl-4-F-phenyln-butoxy Me H H H H H H 3-Cl-4-F-phenyl 2-(Methio)methoxy Me H H H H H H3-Cl-4-F-phenyl O-(3,4-F-benzoyl) Me H H H H H H 3-Cl-4-F-phenyl OAc MeH H H H H H 3-Cl-4-F-phenyl Cl Me H H H H H H 3-Cl-4-F-phenyl OCF2H Me HH H H H H phenylsulfonyl OMs Me H H H H H H 3-Cl-4-F-phenylcarboxymethoxy Me H H H H H H 3-Cl-4-F-phenyl OCF2H Me H H H H H H bromoOCF2H Me H H H H H Bromo H OH Me H H H H H H dimethylcarbinol OCF2H Me HH H H H H 4-Me-phenyl OCF2H Me H H H H H H 3-Me-phenyl OCF2H Me H H H HH 4-Me-phenyl H OCF2H Me H H H H H 3-Me-phenyl H NH2 Me H H H H H H MeOH Me H H H H H CO2Et H OCF2H allyl H H H H H H 3-Cl-4-F-phenyl OH2-Me-2-propene H H H H H H 3-Cl-4-F-phenyl OH Me H H H H HDimethylcarbinol H OH propargyl H H H H H H 3-Cl-4-F-phenyl OH2-bromo-2-propene H H H H H H 3-Cl-4-F OH allyl H H H H H H4-Cl-thiophenoxy OCF2H allyl H H H H H H 4-Cl-thiophenoxy Me2N Me H H HH H H Me NHAc Me H H H H H H Me NH2 allyl H H H H H H 4-Cl-thiophenoxyNHallyl allyl H H H H H H 4-Cl-thiophenoxy NH2 Me H H H H H H bromo2-hydroxyethoxy Me H H H H H H 3-Cl-4-F-phenyl NH2 2,2,2-trifluoroethylH H H H H H 3-Cl-4-F-phenyl NH2 Me H H H H H H phenyl NH2 Me H H H H H H4-MeS-phenyl NH2 Me H H H H H H 4-MeSO2-phenyl NH2 allyl H H H H H H3-Cl-4-F-phenyl NH2 allyl H H H H H H 4-MeSO-phenyl NH2 allyl H H H H HH 4-MeSO2-phenyl NH2 Me H H H H H H 4-dimethylcarbinolphenyl

R⁴ = H; R⁵ = H, R⁶ = H; R⁷ = H R¹ R² R³ OH Me benzyl OH n-butyl benzylOH tert-butyl benzyl OH phenetyl benzyl OH isobutyl benzyl OHα-methylbenzyl benzyl OH benzoyl benzyl OMe benzoyl benzyl OHα-hydroxybenzyl benzyl OH cyclohexylmethyl methyl OH naphthylmethylmethyl OH n-heptyl methyl OH n-butyl methyl OH 3-phenyl-2-propenylmethyl OH 3-phenyl-propyl methyl OH phenethyl methyl OH 1-naphthylmethylmethyl OH 4-(4-Cl-thiophenoxy)benzoyl methyl NH22-(3-Cl-4-F-phenyl)-5-picolyl methyl

R¹ R¹⁴ OH H OMe H OBn H OH Methyl OH Phenyl OMe Phenyl H Phenyl

Another embodiment of the invention encompasses a compound of Formula B

or a pharmaceutically acceptable salt, hydrate, ester or tautomerthereof, wherein:

-   X is selected from a bond, O or S(O)k, wherein k is 0, 1 or 2,-   R¹ is selected from the group consisting of:

(1) hydrogen,

(2) halo,

(3) hydroxy,

(4) C₁₋₆alkyl,

(5) C₁₋₆alkenyl,

(6) C₁₋₆alkoxy,

(7) C₁₋₆alkyl-S(O)_(m)—, wherein m is 0, 1, 2 or 3

(8) C₁₋₆alkyl-C(O)—

(7) C₁₋₆alkoxy-C(O)—

(9) C₁₋₆alkyl-C(O)—O—

(10) aryl,

(11) aralkyl,

(12) aryloxy,

(13) aralkoxy,

(14) arylthio,

(15) aroyl,

(16) aroyloxy and

(17) N(R8)2,

wherein the alkyl , alkenyl and aryl portions of items (4)-(16) aboveare optionally substituted from one up to the maximum number ofsubstituable positions with a member independently selected from thegroup consisting of: halo, heterocycle, C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(k)—,C₁₋₆alkyl-C(O)—, C1-6alkoxy-C(O), C₁₋₆alkyl-C(O)—O, carboxy, hydroxy andaralkoxy, the alkyl portions of said C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(k)—,C₁₋₆alkyl-C(O)—, C₁₋₆alkoxy-C(O) and C₁₋₆alkyl-C(O)—O groups optionallysubstituted with 1-3 substituents independently selected from: halo andhydroxy,said aryl portions of items (10)-(16) above further optionallysubstituted from one up to the maximum number of substituable positionswith C₁₋₆alkyl, optionally substituted with 1-3 substituentsindependently selected from the group consisting of: halo and hydroxy;

-   R³ is selected from the group consisting of:

(1) C₁₋₆alkyl, C₂₋₆alkenyl or C₃₋₆alkynyl, each optionally substitutedwith 1-3 halo groups.

(2) aryl, optionally substituted with 1-3 halo groups,

(3) aralkyl, optionally substituted with a substituent independentlyselected from the group consisting of: C₁₋₆alkylsulfonyl and halo,

-   R⁴, R⁵, R⁶ and R⁷ are each independently selected from the group    consisting of:

(1) hydrogen,

(2) halo, and

(3) C₁₋₆alkyl, optionally substituted with 1-3 halo groups,

-   or R3 and R4 may be joined together with the atoms to which they are    attached to form a monocyclic ring as shown in Formula B′:

wherein R¹⁴ is selected from the groups consisting of: halo, C₁₋₆alkyl,aryl or heterocycle, wherein C₁₋₆alkyl, heterocycle and aryl areoptionally substituted with 1-3 substituents independently selected fromhalo, C₁₋₃alkyl, carboxy, SO₂C₁₋₃alkyl or SO₂N(C₁₋₃alkyl)₂ saidC₁₋₃alkyl is optionally substituted with a hydroxy group, and

-   R⁸ is selected from the group consisting of H, C₁₋₆allyl,    C₁₋₆alkenyl, C₁₋₆alkyl-C(O)— and aryl, the aryl, alkyl and alkenyl    portions are optionally substituted with 1-3 halo groups,-   R₉ and R₁₀ are independently selected from the group consisting of:

(1) halo,

(2) C₁₋₆alkyl,

(3) C₁₋₆alkenyl,

(4) C₁₋₆alkoxy,

(5) C₁₋₆alkyl-S(O)_(k)—, wherein k is 0, 1 or 2,

(6) C₁₋₆alkyl-C(O)—,

(7) C₁₋₆alkoxy-C(O),

(8) C₁₋₆alkyl-C(O)—O—,

(9) carboxy,

(10) hydroxy, and

(11) N(R8)2,

-   wherein the alkyl and alkenyl portions of items (2)-(8) above are    optionally substituted from one up to the maximum number of    substituable positions with a member independently selected from the    group consisting of: halo, heterocycle, C₁₋₆alkoxy,    C₁₋₆alkyl-S(O)_(k)—, C₁₋₆alkyl-C(O)—, C₁₋₆alkoxy-C(O)—,    C₁₋₆alkyl-C(O)—O—, aralkoxy, carboxy and hydroxy, the alkyl portions    of said C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(k)—, C₁₋₆alkyl-C(O)—,    C₁₋₆alkoxy-C(O) and C₁₋₆alkyl-C(O)—O groups optionally substituted    with 1-3 substituents independently selected from halo and hydroxy.

Within this embodiment is encompassed the compound of Formula B wherein:

-   X is selected from a bond, O or S(O)k, wherein k is 0, 1 or 2,-   R¹ is selected from the group consisting of:

(1) halo,

(2) hydroxy,

(3) C₁₋₆alkyl,

(4) C₁₋₆alkoxy, and

(5) N(R⁸)₂, wherein R⁸ is H or C₁₋₄alkyl,

-   wherein the alkyl portions of items (3)-(4) above are optionally    substituted with 1-3 halo groups,-   R³ is C₁₋₆alkyl or C2-4alkenyl, each optionally substituted with 1-3    halo groups.-   R⁴, R⁵, R⁶, R⁷ and R₉ are each H, and R₁₀ is H or halo.

The present invention also encompasses a compound selected from thegroup consisting of:

-   (1)    3-{4-[(4-chlorophenyl)thio]benzyl}-4-hydroxy-1-methylquinolin-2(1H)-one;-   (2)    1-allyl-3-{4-[(4-chlorophenyl)thio]benzyl}-4-hydroxyquinolin-2(1H)-one;-   (3)    1-allyl-4-amino-3-{4-[(4-chlorophenyl)thio]benzyl}quinolin-2(1H)-one;-   (4)    3-[(3′-chloro-4′-fluoro-1,1′-biphenyl4-yl)methyl]-4-hydroxy-1-methylquinolin-2(1H)-one;-   (5)    1-allyl-3-[(3′-chloro-4′-fluoro-1,1′-biphenyl-4-yl)methyl]-4-hydroxyquinolin-2(1H)-one;-   (6)    4-amino-3-[(3′-chloro-4′-fluoro-1,1′-biphenyl-4-yl)methyl]-1-methylquinolin-2(1H)-one;-   (7)    3-[(3′-chloro-4′-fluoro-1,1′-biphenyl-4-yl)methyl]-4-(difluoromethoxy)-1-methylquinolin-2(1H)-one;    and-   (8)    3-{4-[(4-chlorophenyl)sulfonyl]benzyl}-4-hydroxy-1-methylquinolin-2(1H)-one.

Another embodiment of the invention encompasses a pharmaceuticalcomposition comprising a compound of Formula B in combination with apharmaceutically acceptable carrier.

The invention is described using the following definitions unlessotherwise indicated.

The term “halogen” or “halo” includes F, Cl, Br, and I.

The term “alkyl” means linear or branched structures and combinationsthereof, having the indicated number of carbon atoms. Thus, for example,C₁₋₆alkyl includes methyl, ethyl, propyl, 2-propyl, s- and t-butyl,butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The term “alkoxy” means alkoxy groups of a straight, branched or cyclicconfiguration having the indicated number of carbon atoms. C₁₋₆alkoxy,for example, includes methoxy, ethoxy, propoxy, isopropoxy, and thelike.

The term “alkylthio” means alkylthio groups having the indicated numberof carbon atoms of a straight, branched or cyclic configuration.C₁₋₆alkylthio, for example, includes methylthio, propylthio,isopropylthio, and the like.

The term “alkenyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon double bond, wherein hydrogen may be replaced by anadditional carbon-to-carbon double bond. C₂₋₆alkenyl, for example,includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like.

The term “alkynyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon triple bond. C₃₋₆alkynyl, for example, includes ,propenyl, 1-methylethenyl, butenyl and the like.

The term “cycloalkyl” means mono-, bi- or tri-cyclic structures,optionally combined with linear or branched structures, the indicatednumber of carbon atoms. Examples of cycloalkyl groups includecyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl,2-ethyl-1-bicyclo[4.4.0]decyl, and the like.

The term “aryl” is defined as a mono- or bi-cyclic aromatic ring systemand includes, for example, phenyl, naphthyl, and the like.

The term “aralkyl” means an alkyl group as defined above of 1 to 6carbon atoms with an aryl group as defined above substituted for one ofthe alkyl hydrogen atoms, for example, benzyl and the like.

The term “aryloxy” means an aryl group as defined above attached to amolecule by an oxygen atom (aryl-O) and includes, for example, phenoxy,naphthoxy and the like.

The term “aralkoxy” means an aralkyl group as defined above attached toa molecule by an oxygen atom (aralkyl-O) and includes, for example,benzyloxy, and the like.

The term “arylthio” is defined as an aryl group as defined aboveattached to a molecule by an sulfur atom (aryl-S) and includes, forexample, thiophenyoxy, thionaphthoxy and the like.

The term “aroyl” means an aryl group as defined above attached to amolecule by an carbonyl group (aryl-C(O)—) and includes, for example,benzoyl, naphthoyl and the like.

The term “aroyloxy” means an aroyl group as defined above attached to amolecule by an oxygen atom (aroyl-O) and includes, for example,benzoyloxy or benzoxy, naphthoyloxy and the like.

The term “heterocycle” is defined as a 5- to 10-membered aromatic,partially aromatic or non-aromatic mono- or bicyclic ring, containing1-3 heteroatoms selected from O, S and N, and optionally substitutedwith 1-2 oxo groups. Preferably, “heterocycle” is a 5- or 6-memberedaromatic or non-aromatic monocyclic ring containing 1-3 heteroatomsselected from O, S and N, for example, pyridine, pyrimidine, pyridazine,furan, thiophene, thiazole, oxazole, isooxazole and the like, orheterocycle is a 9- or 10-membered aromatic or partially aromaticbicyclic ring containing 1-3 heteroatoms selected from O, S, and N, forexample, benzofuran, benzothiophene, indole, pyranopyrrole, benzopyran,quionoline, benzocyclohexyl, naphtyridine and the like. “Heterocycle”also includes the following: benzimidazolyl, benzofuranyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl,dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.

For purposes of this specification, the following abbreviations have theindicated meanings:

BOC=t-butyloxycarbonyl

Bn=benzyl

CBZ=carbobenzoxy

DCC=1,3-dicyclohexylcarbodiimide

DCM=dichloromethane

DIBAL=diisobutyl aluminum hydride

DIEA=N,N-diisoproylethylamine

DMAP=4-(dimethylamino)pyridine

EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EDTA=ethylenediaminetetraacetic acid, tetrasodium salt hydrate

FAB=fast atom bombardment

FMOC=9-fluorenylmethoxycarbonyl

HMPA=hexamethylphosphoramide

HATU=O-(7-Azabenzotriazol-l-yl)N,N,N′,N′-tetramethyluroniumhexafluorophosphate

HOBt=1-hydroxybenzotriazole

HRMS=high resolution mass spectrometry

ICBF=isobutyl chloroformate

KHMDS=potassium hexamethyldisilazane

LDA=lithium diisopropylamide

MCPBA=metachloroperbenzoic acid

Ms=methanesulfonyl=mesyl

MsO=methanefulfonate=mesylate

NBS=N-bromosuccinimide

NMM=4-methylmorpholine

PCC=pyridinium chlorochromate

PDC=pyridinium dichromate

Ph=phenyl

PPTS=pyridinium p-toluene sulfonate

pTSA=p-toluene sulfonic acid

r.t.=room temperature

rac.=racemic

TfO=trifluoromethanesulfonate=triflate

THF=tetrahydrofuran

TLC=thin layer chromatography

Alkyl group abbreviations

Me=methyl

Et=ethyl

n-Pr=normal propyl

i-Pr=isopropyl

n-Bu=normal butyl

i-Bu=isobutyl

s-Bu=secondary butyl

t-Bu=tertiary butyl

Salts

The pharmaceutical compositions of the present invention comprise acompound of Formula A or B as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm “pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium, and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, and basic ion exchange resins, such as arginine, betaine,caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

It will be understood that in the discussion of methods of treatmentwhich follows, references to the compounds of Formula A or B are meantto also include the pharmaceutically acceptable salts.

Dose Ranges

The magnitude of prophylactic or therapeutic dose of a compound ofFormula A or B will, of course, vary with the nature and the severity ofthe condition to be treated and with the particular compound of FormulaA and its route of administration. It will also vary according to avariety of factors including the age, weight, general health, sex, diet,time of administration, rate of excretion, drug combination and responseof the individual patient. In general, the daily dose from about 0.001mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg toabout 10 mg per kg. On the other hand, it may be necessary to usedosages outside these limits in some cases.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 0.5 mg to 5 g of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain between from about 1 mg to about 2 g of an activeingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500mg, 600 mg, 800 mg, or 1000 mg.

Pharmaceutical Compositions

For the treatment of any of the prostanoid mediated diseases compoundsof Formula A or B may be administered orally, topically, parenterally,by inhalation spray or rectally in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. In addition to the treatment of warm-bloodedanimals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., thecompound of the invention is effective in the treatment of humans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavouring agents, colouring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example, magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredients is mixed withwater-miscible solvents such as propylene glycol, PEGs and ethanol, oran oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more colouringagents, one or more flavouring agents, and one or more sweeteningagents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsion. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavouring and colouringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. Cosolvents suchas ethanol, propylene glycol or polyethylene glycols may also be used.In addition, sterile, fixed oils are conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil maybe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

Compounds of Formula A or B may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ambient temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound of Formula A or B are employed. (Forpurposes of this application, topical application shall include mouthwashes and gargles.) Topical formulations may generally be comprised ofa pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer,preservative system, and emollient.

Utilities

The ability of the compounds of Formula A or B to interact withprostaglandin receptors makes them useful for preventing or reversingundesirable symptoms caused by prostaglandins in a mammalian, especiallyhuman subject. This mimicking or antagonism of the actions ofprostaglandins indicates that the compounds and pharmaceuticalcompositions thereof are useful to treat, prevent, or ameliorate inmammals and especially in humans: Pain, fever and inflammation of avariety of conditions including rheumatic fever, symptoms associatedwith influenza or other viral infections, common cold, low back and neckpain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine,toothache, sprains and strains, myositis, neuralgia, synovitis,arthritis, including rheumatoid arthritis, degenerative joint diseases(osteoarthritis), gout and ankylosing spondylitis, bursitis, burnsincluding radiation and corrosive chemical injuries, sunburns, painfollowing surgical and dental procedures as well as immune andautoimmune diseases. In addition, such a compound may inhibit cellularneoplastic transformations and metastic tumor growth and hence can beused in the treatment of cancer. Compounds of formula A may also be ofuse in the treatment and/or prevention prostaglandin E mediatedproliferation disorders such as may occur in diabetic retinopathy andtumor angiogenesis. Compounds of Formula A or B will also inhibitprostanoid-induced smooth muscle contraction by antagonizing contractileprostanoids or mimicking relaxing prostanoids and hence may be use inthe treatment of dysmenorrhea, premature labor, asthma and eosinophilrelated disorders. It will also be of use in the treatment ofAlzheimer's disease, the treatment of glaucoma, for the prevention ofbone loss (treatment of osteoporosis) and for the promotion of boneformation (treatment of fractures) and other bone diseases such asPaget's disease.

The compounds of the present invention are also useful for treatingneuropathic pain and urinary incontinence.

By virtue of its prostanoid or prostanoid antagonist activity, acompound of Formula A or B will prove useful as an alternative toconventional non-steroidal anti-inflammatory drugs (NSAID'S)particularly where such non-steroidal anti-inflammatory drugs may becontraindicated such as in patients with peptic ulcers, gastritis,regional enteritis, ulcerative colitis, diverticulitis or with arecurrent history of gastrointestinal lesions; GI bleeding, coagulationdisorders including anemia such as hypoprothrombinernia, haemophilia orother bleeding problems; kidney disease; thrombosis, occlusive vasculardiseases; those prior to surgery or taking anti-coagulants. Compounds ofFormula A or B will also be useful as a cytoprotective agent forpatients under chemotherapy.

Combinations with Other Drugs

Compounds of Formula A or B will be useful as a partial or completesubstitute for conventional antiinflammatory or analgesic compounds inpreparations wherein they are presently co-administered with otheragents or ingredients. Thus in further aspects, the inventionencompasses pharmaceutical compositions for treating prostaglandin E2mediated diseases as defined above comprising a non-toxictherapeutically effective amount of the compound of Formula A or B asdefined above and one or more ingredients such as another pain relieverincluding acetaminophen or phenacetin; a COX-2 selective inhibitingagent; a conventional NSAID; a potentiator including caffeine; anH2-antagonist, aluminum or magnesium hydroxide, simethicone, adecongestant including phenylephrine, phenylpropanolamine,pseudophedrine, oxymetazoline, ephinephrine, naphazoline,xylometazoline, propylhexedrine, or levo-desoxyephedrine; anantiitussive including codeine, hydrocodone, caramiphen, carbetapentane,or dextramethorphan; another prostaglandin ligand including misoprostol,enprostil, rioprostil, ornoprostol or rosaprostol; a diuretic; asedating or non-sedating antihistamine. In addition, the inventionencompasses a method of treating prostaglandin E2 mediated diseasescomprising: administration to a patient in need of such treatment anon-toxic therapeutically effective amount of the compound of Formula A,optionally co-administered with one or more of such ingredients aslisted immediately above.

METHODS OF SYNTHESIS

Compounds of the present invention can be prepared according to thefollowing methods.

Compounds of the present invention can be prepared according to themethods described in patent WO 92/04327, published Mar. 19, 1992, U.S.Pat. No. 5,942,522, granted Aug. 24, 1999, U.S. Pat. No. 5,412,104,granted May 2, 1995, U.S. Pat. No. 5,378,694, granted Jan. 3, 1995, allof which are hereby incorporated by reference in their entirety, or bythe following methods:

Method A

The examples may be prepared by reductive alkylation at C3 of thecommercially available N-methyl-4-hydroxy-2-quinolinone with variousaldehydes

using an acid such as TFA or formic acid with a reducing agent such asEt3SiH in a solvent such as toluene, acetonitrile or formic acid.Method B

Compound of formula m (for example alkyl anthranilate oranthranilonitrile) can be used to make amino or hydroxy-quinolinone bysequential alkylation of amino group with alkylating agents such as acidchloride and alkyl halide using standard protocols. Cyclization to thequinolinone can be performed with a base such as potassium tert-butoxidein a solvant such as THF.

Method C

Compound of formula A′ may be prepared by reacting indoline (fromcommercial sources of via reduction of corresponding indoles (see forex. B. F. Bowden et al, Aust. J. Chem., 1975, 28, 65-80) with malonates(see T. Kappe, C. O. Kappe, J. Heterocyclic Chem., 1989, 26, 1555).

REPRESENTATIVE COMPOUNDS

Table 1 illustrates compounds which are representative of the presentinvention.

TABLE 1

Example R¹ R³ R⁴ R⁵ R⁶ R⁷ R¹¹ R¹² R¹³ 1 OMe benzyl H H H H H H H 2 OH4-MeSO2benzyl H H H H H H H 3 OH benzyl H H H H H H 4-MeSO2 4 OH n-butylH H H H H H H 5 Me benzyl H H H H H H H 6 OH iso-propyl H H H H H H H 7OH Me H H H H H H H 8 OH phenyl H H H H H H H 16 OH Me H H H H H H Me 17OH benzyl Me H H H H H H 18 OH ethyl Me H H H H H H 19 OH Me H Cl H H HH phenyl 20 OH Me H H Cl H H H 3-Cl-4-F-phenyl 21 NH2 Me H H H H F H3-Cl-4-F-phenyl 22 OH Me H H H H H H OMe 23 OH Me H H H H H H CO2Me 24OH Me H H H H H CO2H H 25 OH Me H H H H H H CO2H 26 OH Me H H H H H HSMe 27 OH Me H H H H Me H H 28 OH Me H H H H H Me H 29 OH Me H H H H H HOPh 30 OH Me H H H H H H Ph 31 OH Me H H H H H H CF3 32 OH Me H H H H HH F 33 OH Me H H H H H H NMe2 34 OH Me H H H H H H isopropyl 35 OH ethylH H H H H H Me 36 OH Me H H H H H H 3,4-(OCF2H) 37 OH Me H H H H H Hphenylsulfonyl 38 OH Me H H H H H H 4-Cl-thiophenoxy 39 OH Me H H H H HH benzoyl 40 OH Me H H H H H H bromo 41 OH Me H H H H H H3-Cl-4-F-phenyl 42 OCF2H Me H H H H H H phenyl 43 OH Me H H H H H H5-(2-Et-pyridinyl) 44 OH Me H H H H H 5-(2-Et-pyridinyl) H 45 OH Me H HH H H 4-CF3-phenyl H 46 OH Me H H H H H H 4-CF3-phenyl 47 OH Me H H H HH H 4-tert-butylphenyl 48 OH Me H H H H H H 4-acetylphenyl 49 OH Me H HH H H 4-acetylphenyl H 50 OH Me H H H H H H 4-carboxyphenyl 51 OH Me H HH H H H 4-Et-phenyl 52 OH Me H H H H H bromo H 53 OMs Me H H H H H Hphenyl 54 OH Me H H H H H phenyl H 55 OH Me H H H H H 4-carboxyphenyl H56 OH Me H H H H H 4-Cl-phenyl H 57 OH Me H H H H H 3-thienyl H 58 OH MeH H H H H 4-OCF3-phenyl H 59 OH Me H H H H H H 3-thienyl 60 OH Me H H HH H H 2-thienyl 61 OH Me H H H H H H 2-naphthyl 62 OH Me H H H H H H4-Cl-phenyl 63 OH Me H H H H H H 4-OCF3-phenyl 64 OH Me H H H H H H2-benzothiophene 65 OH Me H H H H H H 4-F-phenyl 66 OH Me H H H H H2-F-phenyl H 67 OH Me H H H H H H 4-Me-phenyl 68 OH Me H H H H H H4-benzyloxyphenyl 69 OH Me H H H H H H α-OH-a-Me-benzyl 70 OH Me H H H HH H 1-naphthyl 71 OH Me H H H H H H 2-F-phenyl 72 OH Me H H H H H H3-F-phenyl 73 OH Me H H H H H H 3-Cl-phenyl 74 OH Me H H H H H3-Cl-phenyl H 75 OH Me H H H H H 3-F-phenyl H 76 OH Me H H H H H H4-Cl-phenylsulfonyl 77 OH Me H H H H H H α-OH-a-Me-4-Cl-benzyl 78 OH MeH H H H H H 3-Cl-4-F-phenyl 79 OH ethyl H H H H H H 3-Cl-4-F-phenyl 80OH allyl H H H H H H 3-Cl-4-F-phenyl 81 OH n-propyl H H H H H H3-Cl-4-F-phenyl 82 OH Me H H H H H H 4-MeSO2 83 OH Me H H H H H2-benzothiophene H 84 OH 4-Cl-benzyl H H H H H H 3-Cl-4-F-phenyl 85 NH2Me H H H H H H 3-C1-4-F-phenyl 86 2-(2-pyridinyl)ethoxy Me H H H H H H3-Cl-4-F-phenyl 87 carbethoxymethoxy Me H H H H H H 3-Cl-4-F-phenyl 88n-butoxy Me H H H H H H 3-Cl-4-F-phenyl 89 2-(Methio)ethoxy Me H H H H HH 3-Cl-4-F-phenyl 90 O-(3,4-F-benzoyl) Me H H H H H H 3-Cl-4-F-phenyl 91OAc Me H H H H H H 3-Cl-4-F-phenyl 92 Cl Me H H H H H H 3-Cl-4-F-phenyl93 OCF2H Me H H H H H H phenylsulfonyl 94 OMs Me H H H H H H3-Cl-4-F-phenyl 95 carboxymethoxy Me H H H H H H 3-Cl-4-F-phenyl 96OCF2H Me H H H H H H bromo 97 OCF2H Me H H H H H bromo H 98 OH Me H H HH H H dimethylcarbinol 99 OCF2H Me H H H H H H 4-Me-phenyl 100 OCF2H MeH H H H H H 3-Me-phenyl 101 OCF2H Me H H H H H 4-Me-phenyl H 102 OCF2HMe H H H H H 3-Me-phenyl H 103 NH2 Me H H H H H H Me 104 OH Me H H H H HCO2Et H 105 OCF2H allyl H H H H H H 3-Cl-4-F-phenyl 106 OH2-Me-2-propene H H H H H H 3-Cl-4-F-phenyl 107 OH Me H H H H Hdimethylcarbinol H 108 OH propargyl H H H H H H 3-Cl-4-F-phenyl 109 OH2-bromo-2-propene H H H H H H 3-Cl-4-F 110 OH allyl H H H H H H4-Cl-thiophenoxy 111 OCF2H allyl H H H H H H 4-Cl-thiophenoxy 112 Me2NMe H H H H H H Me 113 NHAc Me H H H H H H Me 114 NH2 allyl H H H H H H4-Cl-thiophenoxy 115 NHallyl allyl H H H H H H 4-Cl-thiophenoxy 116 NH2Me H H H H H H bromo 117 2-hydroxyethoxy Me H H H H H H 3-Cl-4-F-phenyl118 NH2 2,2,2-trifluoroethyl H H H H H H 3-Cl-4-F-phenyl 119 NH2 Me H HH H H H phenyl 120 NH2 Me H H H H H H 4-MeS-phenyl 121 NH2 Me H H H H HH 4-MeSO2-phenyl 122 NH2 allyl H H H H H H 3-Cl-4-F-phenyl 123 NH2 allylH H H H H H 4-MeSO-phenyl 124 NH2 allyl H H H H H H 4-MeSO2-phenyl 125NH2 Me H H H H H H 4-dimethylcarbinolphenyl

Table 2 further illustrates compounds which are representative of thepresent invention.

TABLE 2

R⁴ = H; R⁵ = H, R⁶ = H; R⁷ = H Example R¹ R² R³ 126 OH Me benzyl 127 OHn-butyl benzyl 128 OH tert-butyl benzyl 129 OH phenetyl benzyl 130 OHisobutyl benzyl 131 OH α-methylbenzyl benzyl 132 OH benzoyl benzyl 133OMe benzoyl benzyl 134 OH α-hydroxybenzyl benzyl 135 OH cyclohexylmethylmethyl 136 OH naphthylmethyl methyl 137 OH n-heptyl methyl 138 OHn-butyl methyl 139 OH 3-phenyl-2-propenyl methyl 140 OH 3-phenyl-propylmethyl 141 OH phenethyl methyl 142 OH 1-naphthylmethyl methyl 143 OH4-(4-Cl-thiophenoxy)benzoyl methyl 144 NH2 2-(3-Cl-4-F-phenyl)-5-picolylmethyl

Table 3 further illustrates compounds which are representative of thepresent invention.

TABLE 3

Example R¹ R¹⁴  9 OH H 10 OMe H 11 OBn H 12 OH Methyl 13 OH Phenyl 14OMe Phenyl 15 H Phenyl

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

-   1. All the end products of the Formula A and intermediates were    analyzed by NMR and TLC;-   2. Most compounds were purified by flash chromatography on silica    gel, recrystallization and/or swish (stirring vigorously a    suspension in a solvent followed by filtration of the solid); and-   3. The course of reactions was followed by thin layer chromatography    (TLC) and reaction times are given for illustration only.    General procedure:    Method A

To N-methyl-4-hydroxy-2-quinolone (0.5 g, 2.8 mmol) and an aldehyde (4.3mmol) in toluene (20 mL) at 22° C. was added triethylsilane (1.4 mL, 8.8mmol) and TFA (1.0 ml, 13 mmol). The reaction mixture was stirred atreflux for 3 h, cooled to 22° C. and poured into aqueous NaHCO₃ andextracted with EtOAc. The organic extract was washed (H₂O, brine), dried(MgSO₄), filtered and concentrated. Purification by flash chromatographyor crystallization from hexane-EtOAc (or hexane-Et₂O) afforded the titlecompound.

Method B

Step 1

To a stirred solution of the acyl chloride (1.1 eq) in DCM (0.5 M) atroom temperature was added anthranilonitrile (1 eq). After 15 minute,triethylamine (1.5 eq) was added and the mixture stirred overnight. Theproduct is filtered off and the filtrate is diluted with ethyl acetate,extracted with water and a saturated solution of ammonium chloride.Purification was by flash chromatography or crystallization fromhexane-EtOAc (or hexane-Et₂O).

Step 2

The compound from step 1 was suspended in ThF at room temperature andthen treated with a solution of potassium tert-butoxide in THF (1 eq),stirred 20 minutes then methyl iodide (1 eq) was added, the progress ofthe alkylation is followed by TLC. When completed, the reaction wastreated again with a solution of potassium tert-butoxide in THF (1 eq).After completion by TLC, the reaction mixture is diluted with ethylacetate and water, washed with a saturated solution of ammoniumchloride, a saturated solution of sodium chloride. Purification by flashchromatography or crystallization from hexane-EtOAc (or hexane-Et₂O)afforded the title compound.

EXAMPLE 13

5-Benzyl-6-hydroxy-2-phenyl-1,2-dihydro-pyrrolo[3,2,1-ij]quinolin-4-one

2-Phenylindoline and diethylbenzyl malonate was heated to 140° C. over 1h distilling off EtOH. The mixture was gradually heated up to 280° C.and maintained at this temperature for 2 h. Cooling afforded a solidwhich was stirred vigourously in hot ethyl acetate for 1 h. The desiredcompound was isolated after filtration as a beige solid. m.p. 252-254°C.

EXAMPLE 16

4-hydroxy-1-methyl-3-(4-methylbenzyl)quinolin-2(1H)-one

Following the procedures described in General Method A and using4-methylbenzaldehyde, the title compound was isolated as white powderafter purification by flash chromatography (hexane-ethyl acetate, 8:2).An alternative procedure is General Method B, replacinganthranilonitrile with methyl 2-aminobenzoate and3-(4-methylphenyl)propanoyl chloride.

¹H NMR (400 MHz, acetone-d₆) δ 10.1 (s, OH), 8.09 (d, 1H), 7.56 (t, 1H),7.54 (d, 1H), 7.22 (m, 3H), 7.0 (d, 2H), 4.0 (s, 2H), 3.6 (s, 3H), 2.03(s, 3H).

EXAMPLE 38

3-{4-[(4-chlorophenyl)thio]benzyl}-4-hydroxy-1-methylquinolin-2(1H)-one

Following the procedures described in General Method A and using4-[(4-chlorophenyl)thio]benzaldehyde from example 114, step 1, the titlecompound was isolated as white powder after purification by flashchromatography (hexane-ethyl acetate, 3:2).

¹H NMR (400 MHz, DMSO-d₆): δ 10.5 (s, 1H), 8.02 (d, 1H), 7.62 (t, 1H),7.48 (d, 1H), 7.36 (d, 2H), 7.29 (m, 5H), 7.17 (d, 2H), 3.98 (s, 2H),3.58 (s, 3H).

EXAMPLE 110

1-allyl-3-{4-[(4-chlorophenyl)thio]benzyl}-4-hydroxyquinolin-2(1H)-one

Following the procedures described in Example 114, replacinganthranilonitrile with methyl 2-aminobenzoate in step 1 of GeneralMethod B, the title compound was isolated as white powder afterpurification by flash chromatography (hexane-ethyl acetate, 8:2).

¹H NMR (400 MHz, acetone-d₆) δ 8.03 (d, 1H), 7.55 (t, 1H), 7.43-7.34 (m,4H), 7.30-7.14 (m, 6H), 5.87 (m, 1H), 5.09 (d, 1H), 4.93-4.86 (m, 3H),3.98 (d, 2H).

EXAMPLE 114

1-allyl-4-amino-3-{4-[(4-chlorophenyl)thio]benzyl}quinolin-2(1H)-one

Step 1: 4-[(4-chlorophenyl)thio]benzaldehyde

A solution of 4-fluoro-benzaldehyde (1 eq), 4-chloro-benzenethiol (1.0eq) and sodium carbonate (1.5 eq) in DMF (0.16 M) was heated at 100° C.for 3 h then 18 h at rt. The mixture was diluted with ether and water,the organic phase washed with brine and the solvents evaporated. Theresidue was purified by stirring vigorously in hexane-ether followed byfiltration to give the title compound as a white solid.

Step 2: methyl (2E)-3-{4-[(4-chlorophenyl)thio]phenyl}prop-2-enoate

A solution of aldehyde (1 eq) from step 1 and methyltriphenylphosphoranylidene acetate (1.4 eq) in toluene (0.3M) was heatedat 100° C. for 4 h. After evaporation of the solvents, the residue waspurified by flash chromatography (hexane-ethyl acetate, 9:1) to give thetitle compound as a white solid.

Step 3: methyl 3-{4-[(4-chlorophenyl)thio]phenyl}propanoate

A solution of ester from step 2 in EtOAc (0.2M) containing 10% Pd/C(0.15 g/mmol) was agitated under hydrogen (50 psi, Parr apparatus) for 3h. The mixture was filtered over Celite and the solvent evaporated toafford the title compound.

Step 4: 3-{4[(4-chlorophenyl)thio]phenyl}propanoic acid

A solution of ester from step 3 and LiOH (2N, 3 eq) in MeOH (0.2M) wasstirred at reflux for 2 h, cooled to rt and acidified to pH 3 with HCl10%. The mixture was extracted with ether and the solvent evaporated.The residue was purified by stirring vigorously in hexane followed byfiltration to give the title compound as a white solid.

Step 5: 3-{4-[(4-chlorophenyl)thio]phenyl}propanoyl chloride

To a solution of acid from step 4 in CH₂Cl₂ (0.2M) was added oxalylchloride (1.2 eq) and one drop of DMF. The mixture was stirred at rt for3 h and the solvent evaporated. The crude acid chloride was used as suchin the next step.

Step 6:1-allyl-4-amino-3-{4-[(4-chlorophenyl)thio]benzyl}quinolin-2(1H)-one

Following the procedures described in General Method B, using acidchloride from previous step 5 and replacing methyl iodide by allylbromide in step 2 of General Method B, the title compound was isolatedas white foam after purification by flash chromatography (hexane-ethylacetate, 8:2).

¹H NMR (400 MHz, acetone-d₆) δ 7.95 (dd, 1H), 7.52 (dt, 1H), 7.39 (m,3H), 7.30 (m, 4H), 7.20 (m, 3H), 5.98-5.92 (m, 1H), 5.81 (s, 2H),5.12-5.0 (m, 2H), 4.97 (m, 2H), 4.07 (s, 2H).

EXAMPLE 145

3-[(3′-chloro-4′-fluoro-1,1′-biphenyl-4-yl)methyl]-4-hydroxy-1-methylquinolin-2(1H)-one

Following the procedures described in General Method A and using4-[(3-chloro-4-fluorophenyl)]benzaldehyde, stirring vigorously theresidue in acetone followed by filtration, the title compound wasisolated as white powder.

EXAMPLE 146

1-allyl-3-[(3′-chloro-4′-fluoro-1,1′-biphenyl-4-yl)methyl]4-hydroxyquinolin-2(1H)-one

Following the procedures described in Example 110, the title compoundwas isolated as white powder after purification by flash chromatography(hexane-ethyl acetate, 8:2) and stirring vigorously the residue in etherfollowed by filtration.

¹H NMR (400 MHz, acetone-d₆) δ 10.6 (s, OH), 8.04 (d, 1H), 7.79 (dd,1H), 7.61 (m, 1H), 7.54-7.31 (m, 7H), 7.23 (t, 1H), 5.88 (m, 1H), 5.09(d, 1H), 4.92 (d, 1H), 4.87 (s, 2H), 4.02 (s, 2H).

EXAMPLE 147

4-amino-3-[(3′-chloro-4′-fluoro-1,1′-biphenyl-4-yl)methyl]-1-methylquinolin-2(1H)-one

Following the procedures described in Example 114, the title compoundwas isolated as white powder after purification by flash chromatography(hexane-ethyl acetate, 8:2) and stirring vigorously the residue in etherfollowed by filtration.

¹H NMR (300 MHz, CDCl₃): δ 7.58-7.49 (m, 3H), 7.41-7.24 (m, 6H),7.21-7.11 (m, 2H), 4.45 (s, NH₂), 4.11 (s, 2H), 3.74 (s, 3H).

EXAMPLE 148

3-[(3′-chloro-4′-fluoro-1,1′-biphenyl-4-yl)methyl]-4-(difluoromethoxy)-1-methylquinolin-2(1H)-one

A solution of example 145, Cs₂CO₃ (2 eq) in DMF (0.2M) was heated at100° C. (open flask) then methyl chlorodifluoroacetate (2 eq) was addedand the mixture stirred at 90-110° C. for 3 h. After cooling to rt, themixture was diluted with water, extracted with ethyl acetate and thesolvent evaporated. The residue was purified by crystallisation inhexane\ether to give the title compound as a white powder.

¹H NMR (400 MHz, acetone-d₆) δ 7.89 (d, 1H), 7.76-7.68 (m, 2H),7.65-7.52 (m, 4H), 7.48-7.33 (m, 4H), 7.05 (t, 1H), 4.15 (s, 2H), 3.75(s, 3H).

EXAMPLE 149

3-{4-[(4-chlorophenyl)sulfonyl]benzyl}-4-hydroxy-1-methylquinolin-2(1H)-one

Step 1: 4-[(4-chlorophenyl)sulfonyl]benzaldehyde

A solution of 4-[(4-chlorophenyl)thio]benzaldehyde from example 114,step1 and mCPBA (2.2 eq) in CH₂Cl₂ was stirred at rt for 1 h thenCa(OH)₂ (2.2 eq) was added. The mixture was stirred 30 min, filtered andthe solvent evaporated. The residue was purified by stirring vigorouslyin hexane-ether followed by filtration to give the title compound as awhite solid.

Step2:3-{4-[(4-chlorophenyl)sulfonyl]benzyl}4-hydroxy-1-methylquinolin-2(1H)-one

Following the procedures described in General Method A and usingaldehyde from step 114, the title compound was isolated as white powderafter purification by stirring vigorously in ethylacetate-chloroform-ether followed by filtration.

¹H NMR (400 MHz, DMSO-d₆): δ 10.6 (s, 1H), 8.02 (d, 1H), 7.90 (d, 2H),7.82 (d, 2H), 7.65 (d, 2H), 7.58 (dt, 1H), 7.44 (m, 3H), 7.25 (t, 1H),4.03 (s, 2H), 3.54 (s, 3H).

ASSAYS FOR DETERMINING BIOLOGICAL ACTIVITY

The compound of Formula A can be tested using the following assays todetermine their prostanoid antagonist or agonist activity in vitro andin vivo and their selectivity. The prostaglandin receptor activitiesdemonstrated are DP, EP₁, EP₂, EP₃, EP₄, FP, IP and TP.

Stable Expression of Prostanoid Receptors in the Human Embryonic Kidney(HEK) 293(ebna) Cell Line

Prostanoid receptor cDNAs corresponding to full length coding sequencesare subcloned into the appropriate sites of mammalian expression vectorsand transfected into HEK 293(ebna) cells. HEK 293(ebna) cells expressingthe individual cDNAs are grown under selection and individual coloniesare isolated after 2-3 weeks of growth using the cloning ring method andsubsequently expanded into clonal cell lines.

Prostanoid Receptor Binding Assays

HEK 293(ebna) cells are maintained in culture, harvested and membranesare prepared by differential centrifugation, following lysis of thecells in the presence of protease inhibitors, for use in receptorbinding assays. Prostanoid receptor binding assays are performed in 10mM MES/KOH (pH 6.0) (EPs, FP and TP) or 10 mM HEPES/KOH (pH 7.4) (DP andIP), containing 1 mM EDTA, 10 mM divalent cation and the appropriateradioligand. The reaction is initiated by addition of membrane protein.Ligands are added in dimethylsulfoxide which is kept constant at 1%(v/v) in all incubations. Non-specific binding is determined in thepresence of 1 μM of the corresponding non-radioactive prostanoid.Incubations are conducted for 60 min at room temperature or 30° C. andterminated by rapid filtration. Specific binding is calculated bysubtracting non specific binding from total binding. The residualspecific binding at each ligand concentration is calculated andexpressed as a function of ligand concentration in order to constructsigmoidal concentration-response curves for determination of ligandaffinity.

Prostanoid Receptor Agonist and Antagonist Assays

Whole cell second messenger assays measuring stimulation (EP₂EP₄, DP andIP in HEK 293(ebna) cells) or inhibition (EP₃ in human erythroleukemia(HEL) cells) of intracellular cAMP accumulation or mobilization ofintracellular calcium (EP₁, FP and TP in HEK 293(ebna) cells stablytransfected with apo-aequorin) are performed to determine whetherreceptor ligands are agonists or antagonists. For cAMP assays, cells areharvested and resuspended in HBSS containing 25 mM HEPES, pH 7.4.Incubations contain 100 μM RO-20174 (phosphodiesterase type IVinhibitor, available from Biomol) and, in the case of the EP₃ inhibitionassay only, 15 μM forskolin to stimulate cAMP production. Samples areincubated at 37° C. for 10 min, the reaction is terminated and cAMPlevels are then measured. For calcium mobilization assays, cells arecharged with the co-factors reduced glutathione and coelenterazine,harvested and resuspended in Ham's F12 medium. Calcium mobilization ismeasured by monitoring luminescence provoked by calcium binding to theintracellular photoprotein aequorin. Ligands are added indimethylsulfoxide which is kept constant at 1% (v/v) in all incubations.For agonists, second messenger responses are expressed as a function ofligand concentration and both EC₅₀ values and the maximum response ascompared to a prostanoid standard are calculated. For antagonists, theability of a ligand to inhibit an agonist response is determined bySchild analysis and both K_(B) and slope values are calculated.

Rat Paw Edema Assay

The method is the same as described in Chan et al (J. Pharmacol. Exp.Ther. 274: 1531-1537, 1995).

LPS-Induced Pyrexia in Conscious Rats

The method is the same as described in Chan et al (J. Pharmacol. Exp.Ther. 274: 1531-1537, 1995).

LPS-Induced Pyrexia in Conscious Squirrel Monkeys

The method is the same as described in Chan et al (Eur. J. Pharmacol.327: 221-225, 1997).

Acute Inflammatory Hyperalgesia Induced by Carrageenan in Rats

The method is the same as described in Boyce et al (Neuropharmacology33: 1609-1611, 1994).

Adjuvant-Induced Arthritis in Rats

Female Lewis rats (body weight ˜146-170 g) are weighed, ear marked, andassigned to groups (a negative control group in which arthritis was notinduced, a vehicle control group, a positive control group administeredindomethacin at a total daily dose of 1 mg/kg and four groupsadministered with a test compound at total daily doses of 0.10-3.0mg/kg) such that the body weights were equivalent within each group. Sixgroups of 10 rats each were injected into a hind paw with 0.5 mg ofMycobacterium butyricum in 0.1 mL of light mineral oil (adjuvant), and anegative control group of 10 rats was not injected with adjuvant. Bodyweights, contralateral paw volumes (determined by mercury displacementplethysmography) and lateral radiographs (obtained under Ketamine andXylazine anesthesia) were determined before (day-1) and 21 daysfollowing adjuvant injection, and primary paw volumes were determinedbefore (day-1) and on days 4 and 21 following adjuvant injection. Therats were anesthetized with an intramuscular injection of 0.03-0.1 mL ofa combination of Ketamine (87 mg/kg) and Xylazine (13 mg/kg) forradiographs and injection of adjuvant. The radiographs were made of bothhind paws on day 0 and day 21 using the Faxitron (45 kVp, 30 seconds)and Kodak X-OMAT TL film, and were developed in an automatic processor.Radiographs were evaluated for changes in the soft and hard tissues byan investigator who was blinded to experimental treatment. The followingradiographic changes were graded numerically according to severity:increased soft issue volume (0-4), narrowing or widening of joint spaces(0-5) subchondral erosion (0-3), periosteal reaction (0-4), osteolysis(0-4) subluxation (0-3), and degenerative joint changes (0-3). Specificcriteria were used to establish the numerical grade of severity for eachradiographic change. The maximum possible score per foot was 26. A testcompound at total daily doses of 0.1, 0.3, 1and 3 mg/tg/day,indomethacin at a total daily dose of 1 mg/kg/day, or vehicle (0.5%methocel in sterile water) were administered per os b.i.d. beginningpost injection of adjuvant and continuing for 21 days. The compounds areprepared weekly, refrigerated in the dark until used, and vortex mixedimmediately prior to administration.

1. A compound of Formula B

or a pharmaceutically acceptable salt, hydrate, ester or tautomerthereof, wherein: X is selected from a bond, O or S(O)k, wherein k is 0,1 or 2, R¹ is selected from the group consisting of: (1) hydrogen, (2)halo, (3) hydroxy, (4) C₁₋₆alkyl, (5) C₁₋₆alkenyl, (6) C₁₋₆alkoxy, (7)C₁₋₆alkyl-S(O)_(m)—, wherein m is 0, 1, 2 or 3 (8) C₁₋₆alkyl-C(O)— (7)C₁₋₆alkoxy-C(O)— (9) C₁₋₆alkyl-C(O)—O— (10) aryl, (11) aralkyl, (12)aryloxy, (13) aralkoxy, (14) arylthio, (15) aroyl, (16) aroyloxy andwherein the alkyl , alkenyl and aryl portions of items (4)-(16) aboveare optionally substituted from one up to the maximum number ofsubstituable positions with a member independently selected from thegroup consisting of: halo, heterocycle, C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(k)—,C₁₋₆alkyl-C(O)—, C₁₋₆alkoxy-C(O), C₁₋₆alkyl-C(O)—O, carboxy, hydroxy andaralkoxy, the alkyl portions of said C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(k)—,C₁₋₆alkyl-C(O)—, C₁₋₆alkoxy-C(O) and C₁₋₆alkyl-C(O)—O groups optionallysubstituted with 1-3 substituents independently selected from: halo andhydroxy, said aryl portions of items (10)-(16) above further optionallysubstituted from one up to the maximum number of substituable positionswith C₁₋₆alkyl, optionally substituted with 1-3 substituentsindependently selected from the group consisting of: halo and hydroxy;R³ is selected from the group consisting of: (1) C₁₋₆alkyl, C₂₋₆alkenylor C₃₋₆alkynyl, each optionally substituted with 1-3 halo groups. (2)aryl, optionally substituted with 1-3 halo groups, (3) aralkyl,optionally substituted with a substituent independently selected fromthe group consisting of: C₁₋₆alkylsulfonyl and halo, R⁴, R⁵, R⁶ and R⁷are each independently selected from the group consisting of: (1)hydrogen, (2) halo, and (3) C₁₋₆alkyl, optionally substituted with 1-3halo groups, R⁸ is selected from the group consisting of H, C₁₋₆alkyl,C₁₋₆alkenyl, C₁₋₆alkyl-C(O)—and aryl, the aryl, alkyl and alkenylportions are optionally substituted with 1-3 halo groups, R⁹ and R¹⁰ areindependently selected from the group consisting of: (1) halo, (2)C₁₋₆alkyl, (3) C₁₋₆alkenyl, (4) C₁₋₆alkoxy, (5) C₁₋₆alkyl-S(O)_(k)—,wherein k is 0, 1 or 2, (6) C₁₋₆alkyl-C(O)—, (7) C₁₋₆alkoxy-C(O), (8)C₁₋₆alkyl-C(O)—O—, (9) carboxy, (10) hydroxy, and (11) N(R8)2, whereinthe alkyl and alkenyl portions of items (2)-(8) above are optionallysubstituted from one up to the maximum number of substituable positionswith a member independently selected from the group consisting of: halo,heterocycle, C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(k)—, C₁₋₆alkyl-C(O)—,C₁₋₆alkoxy-C(O)—, C₁₋₆alkyl-C(O)—O—, aralkoxy, carboxy and hydroxy, thealkyl portions of said C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(k)—, C₁₋₆alkyl-C(O)—,C₁₋₆alkoxy-C(O) and C₁₋₆alkyl-C(O)—O groups optionally substituted with1-3 substituents independently selected from halo and hydroxy.
 2. Thecompound according to claim 1 wherein: X is selected from a bond, O orS(O)k, wherein k is 0, 1 or 2, R¹ is selected from the group consistingof: (1) halo, (2) hydroxy, (3) C₁₋₆alkyl, (4) C₁₋₆alkoxy, and (5)N(R⁸)₂, wherein R⁸ is H or C₁₋₄alkyl, wherein the alkyl portions ofitems (3)-(4) above are optionally substituted with 1-3 halo groups, R³is C₁₋₆alkyl or C₂₋₄alkenyl, each optionally substituted with 1-3 halogroups. R⁴, R⁵, R⁶, R⁷ and R⁹ are each H, and R¹⁰ is H or halo.
 3. Thecompound according to claim 2 selected from the group consisting of: (1)3-{4-[(4-chlorophenyl)thio]benzyl}-4-hydroxy-1-methylquinolin-2(1H)-one;(2)1-allyl-3-{4-[(4-chlorophenyl)thio]benzyl}-4-hydroxyquinolin-2(1H)-one;(3)1-allyl-4-amino-3-{4-[(4-chlorophenyl)thio]benzyl}quinolin-2(1H)-one;(4)3-[(3′-chloro-4′-fluoro-1,1′-biphenyl-4-yl)methyl]-4-hydroxy-1-methylquinolin-2(1H)-one;(5)1-allyl-3-[(3′-chloro-4′-fluoro-1,1′-biphenyl-4-yl)methyl]-4-hydroxyquinolin-2(1H)-one;(6)4-amino-3-[(3′-chloro-4′-fluoro-1,1′-biphenyl-4-yl)methyl]-1-methylquinolin-2(1H)-one;(7)3-[(3′-chloro-4′-fluoro-1,1′-biphenyl-4-yl)methyl]-4-(difluoromethoxy)-1-methylquinolin-2(1H)-one;and (8)3-{4-[(4-chlorophenyl)sulfonyl]benzyl}-4-hydroxy-1-methylquinolin-2(1H)-one.4.4-amino-3-[(3′-chloro-4′-fluoro-1,1′-biphenyl-4-yl)methyl]-1-methylquinolin-2(1H)-one;or a pharmaceutically acceptable salt thereof.
 5. A pharmaceuticalcomposition comprising the compound of claim 1 and a pharmaceuticallyacceptable carrier.
 6. A pharmaceutical composition comprising thecompound of claim 4 and a pharmaceutically acceptable carrier.